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Preface
Stephen H. Caldwell, MD Arun J. Sanyal, MD
Guest Editors
Few fields of medicine have changed as rapidly as that of hepatology in the past fifteen to
twenty years. However, the management of coagulation disorders, an inherent aspect of
all types of progressive liver failure, seemed to lag behind other areas for a long time and
has remained mired in old dogma and unproven practice guidelines often guided more
by legal concerns than by scientific evidence or rational reason. This situation has now
changed dramatically over the past several years, with a number of welcome advances
ushered in by landmark papers from Tripodi and colleagues, the development of new
therapeutics and with it the improved understanding of normal hemostasis. Additional
refinements in diagnostic tests have been greatly advanced by the pioneering work of
Burroughs and colleagues. These advances have led to the appreciation of the multifac-eted aspects of coagulation disorders in liver disease fromhypo-coagulable tohyper-
coagulable states and the limitations of conventional tests, such as the INR, to shed light
on relative bleeding risk or on underlying pathophysiology in a given patient.
In this issue ofClinics in Liver Disease, we are very happy to present a collection of
original articles from leaders in the field, and from multiple disciplines, from around the
world. Each article discusses the state of the art along with its limitations. Our aim is to
shed light on recent advances and to explore areas of controversy and, thus, the need
for combined clinical and laboratory investigation. We hope this issue will stimulate fur-
ther research on this important issue in liver diseases.
Stephen H. Caldwell, MDGI/Hepatology Division
Digestive Health Center of Excellence
University of Virginia Medical Center
Box 800708, Charlottesville, VA 22908-0708
Arun J. Sanyal, MD
Division of GI/Hepatology and Nutrition
Department of Internal Medicine
VCU School of Medicine
MCV Box 980341, Richmond VA 23298-0341
E-mail addresses:
[email protected](S.H. Caldwell)
[email protected](A.J. Sanyal)
Coagulation and Hemostasis in Liver Disease: Controversies and Advances
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The Coag ulationCasc ade in Cirrhosis
Dougald M. Monroe, PhDa, MaureaneHoffman,MD, PhDa,b,c,*
In the 1960s, two groups proposed a waterfall or cascade model of coagulationcomposed of a sequential series of steps in which activation of one clotting factor
led to the activation of another, finally leading to a burst of thrombin generation.1,2
Each clotting factor was thought to exist as a precursor that could be converted pro-
teolytically into an active enzyme.3 The original models were modified to eventually
become the familiar Y-shaped scheme that we call the coagulation cascade today
(Fig. 1). The two arms of the Y are the intrinsic and extrinsic pathways initiated
by factor XII (FXII) and FVIIa/tissue factor (TF), respectively. The pathways converge on
a common pathway at the level of the FXa/FVa (prothrombinase) complex.
This cascade was not proposed as a literal model of hemostasis in vivo, but rather
as a scheme of how the many identified coagulation factors interact biochemically.However, the lack of any other clear and predictive model of physiologic hemostasis
has meant that most physicians view the cascade as a model of physiology by
default. This view has been reinforced by the fact that screening coagulation tests
(prothrombin time [PT] and activated partial thromboplastin time [aPTT]) are often
used as though they were predictive of clinical bleeding.
Many people recognized that the cascade model had serious failings as a model
of physiologic coagulation, and that the intrinsic and extrinsic systems could not
operate as independent and redundant pathways as implied by this model. It was
also recognized fromthe earliest studies of coagulation that cells are important partic-
ipants in the process4,5 and that normal hemostasis is not possible in the absence of
cell-associated tissue factor (TF) and platelets. It is therefore logical that substituting
the role of cells in in vitro coagulation tests with phospholipid vesicles6 in the PT and
PTT assays overlooks their active roles in hemostasis in vivo. Therefore, we proposed
a Carolina Cardiovascular Biology Center, Department of Medicine, University of NorthCarolina, Chapel Hill, NC, USAb Pathology and Laboratory Medicine Service, Durham Veterans Affairs Medical Center, 508
Fulton Street, Durham, NC 27705, USAc Department of Pathology, Duke University Medical Center, Durham, NC, USA* Corresponding author. Pathology and Laboratory Medicine Service (113), Durham VeteransAffairs Medical Center, 508 Fulton Street, Durham, NC.E-mail address: [email protected](M. Hoffman).
KEYWORDS
Hemostasis Hemorrhage Thrombin Platelets Coagulation factors
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a cell-based model of coagulation7 in which hemostasis occurs in a step-wise process
on cell surfaces, as described below.
STEP1: INITIATION OF COAGULATION ON TISSUE FACTOR^ BEARING CELLS
The coagulation process is initiated when TF-bearing cells are exposed to blood at
a site of injury. TF is a transmembrane protein that acts as a receptor and cofactorfor FVII. It is normally expressed only on cells outside the vasculature. TF is particularly
expressed by the adventitial cells around vessels, where it forms a hemostatic enve-
lope to stop bleeding in the event of vascular injury.8 Once bound to TF, zymogen FVII
is rapidly activated to FVIIa.9 The FVIIa/TF complex catalyzes activation of both FX and
FIX.10 The FXa formed on the TF-bearing cell interacts with its cofactor FVa to gener-
ate a small amount of thrombin on the TF cells.11
Most of the coagulation factors can leave the vasculature, percolate through the
extravascular space, and collect in the lymph.12 We have recently provided histologic
data supporting the view that most TF is bound to FVIIa even in the absence of an in-
jury.13 Therefore, it is likely that low levels of FIXa, FXa, and thrombin are produced onTF-bearing cells at all times.14 However, these activated factors are separated from
other key components of the coagulation system by an intact vessel wall. Platelets
and FVIII bound to von Willebrand factor (vWF) are so large that they only enter the
extravascular compartment when an injury disrupts the vessel wall. When a vessel
is disrupted, platelets escape from the vessel, bind to collagen and other extracellular
matrix components at the site of injury, and are partially activated. This process forms
Fig.1. The coagulation cascade. This model accurately represents the reactions as they occur
in the common clinical coagulation tests, the prothrombin time (PT), and activated partialthromboplastin time (aPTT).
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a platelet plug that provides primary hemostasis. At that point, the small amounts of
thrombin produced on TF-bearing cells can interact with platelets and FVIII/vWF to
initiate the hemostatic process that ultimately enmeshes the initial platelet plug in
a stable fibrin clot (secondary hemostasis).
STEP 2: AMPLIFICATION OF THE PROCOAGULANT SIGNAL BY THROMBIN GENERATED
ON THE TISSUE FACTOR^ BEARING CELL
During theAmplification Step, the small amounts of thrombin formed on TF-bearing
cells promote maximal platelet activation15 and also activate additional coagulation
cofactors on the platelet surface. Although this small amount of thrombin may not
be sufficient to clot fibrinogen, it is sufficient to prime the clotting system for a sub-
sequent burst of platelet surface thrombin generation by activating FV, FVIII, and FXI
on the platelet surface.1618 Thrombin activation of FXI on platelet surfaces explains
why FXII is not needed for normal hemostasis. FIXa activated both on the TF-bearing
cell and by platelet surface FXIa binds to FVIIIa on the platelet surface to assembleFIXa/FVIIIa (tenase) complexes.
STEP 3: PROPAGATION OF THROMBIN GENERATION ON THE PLATELET SURFACE
The burst of thrombin generation needed for effective hemostasis is produced on plate-
let surfaces during the Propagation Phase of coagulation. Once the platelet tenase
complex is assembled, FX from the plasma begins to be activated to FXa on the platelet
surface. FXa then associates with FVa to produce a burst of thrombin generation of suf-
ficient magnitude to stabilize the initial platelet plug in a durable meshwork of fibrin.
Even though the cell-based model depicts the hemostatic process as occurring indiscrete steps, these should be viewed as an overlapping continuum of events. For
example, thrombin produced on the platelet surface early in the propagation phase
may initially cleave substrates on the platelet surface and continue to amplify the pro-
coagulant response, in addition to leaving the platelet and promoting fibrin assembly.
The cell-based model of coagulation shows us that the extrinsic and intrinsic
pathways are not redundant. As shown in Fig. 2, the extrinsic pathway operates on
the TF-bearing cell to initiate and amplify coagulation. By contrast, components of the
intrinsic pathway operate on the activated platelet surface to produce the burst of
thrombin that causes formation and stabilization of the fibrin clot. Thus, the PT assay
tests the levels of procoagulants involved in the Initiation phase of coagulation, whilethe aPTT tests the levels of procoagulants involved in producing the platelet-surface
mediated burst of thrombin generation during the Propagation phase. Neither assay
gives a complete picture of hemostatic function and neither assay includes cellular
components.
THE CRITICAL ROLE OF PLASMA PROTEASE INHIBITORS
Our discussion of the cell-based model highlights another feature of hemostasis that is
not obvious in the cascade model: the importance of the coagulation protease inhibi-
tors. The intrinsic and extrinsic pathways are needed to produce activated FX onthe two different cell surfaces because the presence of coagulation protease inhibitors
tends to localize FXa activity to the surface on which it is formed. FXa on a surface is
relatively protected from inhibition by it principal inhibitors, antithrombin (AT) and tissue
factor pathway inhibitor (TFPI).19 However, FXa in solution is rapidly inhibited, with
a half-life counted in seconds to minutes.20 On the other hand, deficiency of AT is asso-
ciated with a significant thrombotic tendency. Thus, coagulation inhibitors are a critical
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control mechanism, limiting and localizing FXa activity and thrombin generation to a site
of injury. Because the coagulation cascade model was developed in an era more con-
cerned with understanding how thrombin generation occurs than how it is controlled,
this model does not assess the importance of inhibitors. As we shall see, the role ofinhibitors has great relevance to certain aspects of the pathology of the coagulation
system in liver disease.
THE PROTEIN C /S /THROMBOMODULIN SYSTEM PROVIDES PROTECTION FROM THROMBOSIS
Proteins C and S are vitamin Kdependent factors synthesized by hepatic parenchymal
cells.21 Protein C is the precursor of a protease,22 while Protein S is a nonenzymatic
Fig. 2. (Top Panel) A comparison of the extrinsic pathway in the prothrombin time (PT) as-say and on TF-bearing cells. On the left, the proteins of the extrinsic pathway of the coag-ulation cascade are shown. In the PT, relipidated TF or a tissue extract containing TF is the
reagent added to initiate clotting. Deficiency of any of the subsequent proteins prolongsthe PT. On the right, the Initiation Phase of coagulation in vivo is illustrated. FVIIa boundto tissue factor activates both FX and FIX on the surface of a TF-bearing cell. FXa formedby FVIIa/TF binds to FVa on that cell and converts a small amount of prothrombin to throm-bin. (Bottom Panel) A comparison of the intrinsic pathway in the activated partial throm-boplastin time (aPTT) and on activated platelets. On the left, the proteins of the intrinsicpathway in the coagulation cascade are shown, with the sequence of activation proceed-ing from high molecular weight kininogen (HK) and prekallekrein (PK). Coagulation in theaPTT is initiated by the addition of a charged surface, such as kaolin or diatomaceous earth,to which HK, PK, and FXII bind and become activated. Deficiency of any of the listed factorsprolongs an aPTT assay. However, deficiency of HK, PK, or FXII is not associated with a bleed-ing tendency. On the right, the role of the proteins of the intrinsic pathway in the Propaga-tion Phase of coagulation in vivo is illustrated. On the surface of an activated platelet, FIXaformed on the TF-bearing cell can bind to FVIIIa to form an Xase complex. Additional FIXa isformed by platelet-bound FXIa. FXa formed on the platelet surface is channeled into IIasecomplexes, leading to a burst of thrombin generation.
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cofactor that enhances the activity of activated Protein C (aPC). While they are often
called anticoagulant, they primarily serve the specific function of preventingnormal
endothelial lining cells from serving as a site for thrombin generation (Fig. 3).23 This is
an important function, since propagation of thrombin generation on the intact endothe-
lium can lead to thrombosis. Thus, this is truly more of an antithrombotic than
anticoagulant function.
Protein C from the plasma is localized to endothelial cell surfaces by a specific endo-
thelial protein C receptor (EPCR).24 Thrombomodulin (TM) is a cell surface receptor for
thrombin that is also found on normal healthy endothelial cells.25 When thrombin
escapes from a site of injury onto nearby intact endothelial cells, it is bound by TM.
The thrombin/TM complex can no longer carry out procoagulant functions,26 such as
clotting fibrinogen or activating platelets, but rather the complex activates protein C
(aPC), which then binds to protein S. The complex cleaves and inactivates any FV
that has been activated on the endothelial surface.27 Because FVa is essential for acti-
vation of prothrombin by FXa, inactivation of FVa disables thrombin production on the
endothelial surface and prevents propagation of the procoagulant reactions throughout
the vascular tree. The aPC/Protein S complex can also inactivate FVIIIa,28 but the phys-
iologic importance of this activity is not completely clear.
WHAT HAPPENS TO THE COAGULATION SYSTEM IN LIVER DISEASE?
Because most of the pro- and anticoagulant proteins are synthesized by hepatic
parenchymal cells, it is easy to understand how advanced liver disease can disrupt he-
mostatic function. All of the procoagulant factors except FVIII are reduced in hepatic
insufficiency. By contrast, the level of FVIII/vWF is increased, often very dramatically,in cirrhosis.29 Since all of the components in the extrinsic pathway are produced by
hepatocytes, the degree of prolongation of the PT has been used extensively as a mea-
sure liver synthetic function.
However, not only are the procoagulant factors reduced, but also the levels of
protease inhibitors and Proteins C and S are reduced in hepatic insufficiency,30,31 a sit-
uation that is notreflected in the PT or aPTT. Thus, we measure only the procoagulant
side of the hemostatic equation with the common clotting tests. Yet, it is the balance
between pro- and anticoagulant/antithrombotic activities that ultimately determines
whether bleeding, thrombosis, or appropriate hemostasis occurs.
Several groups have tried to understand and assess facets of hemostasis in liverdisease. Some tests that may give a better view of the overall hemostatic balance
Fig. 3. Thrombin on an endothelial cell has antithrombotic function by activating protein C.The aPC/protein S complex cleaves and inactivates FVa and FVIIIa to prevent propagation ofthrombin generation on intact endothelium. Thrombin that diffuses off of the surface is in-activated by the protease inhibitor antithrombin (AT).
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in liver disease will be discussed in succeeding chapters. However, on a conceptual
level, the hemostatic balance in liver disease can be thought of not as intrinsically
pro- or anticoagulant, but rather as a state in which there is a reduced ability to main-
tain this balance. In other words, the coagulation system can be conceived as a buff-
ered system in which a tendency to activation of the system is countered (buffered) by
the action of plasma protease inhibitors and negative feedback loops. It is clear that
the normal plasma levels of the coagulation factors are well above the level needed
for adequate function. For most of the procoagulants only 20% to 50% of the normal
level is actually required for hemostasis. It seems likely that this excess provides
a margin of safety in accommodating physiologic and pathophysiologic events that
consume factors or otherwise stress the system. In healthy individuals, sufficient
levels of pro- and anticoagulant factors still remain after a perturbation to maintain nor-
mal hemostasis.
Similarly, when liver parenchymal damage leads to a relatively balanced reduction in
both pro- and anticoagulant proteins, the net result is that there is very little change in
the ability of the system to generate hemostatic levels of thrombin.32 Thus, in the
absence of a significant perturbation, patients with liver failure do not necessarily
have a hemorrhagic tendency or, conversely, evidence of ongoing activation of coag-
ulation.33 However, when the system is stressed, for example by infection,34 the lim-
ited buffering capacity makes the system fragile and prone to be tipped out of
balance into either a state of hemorrhage or thrombosis/disseminated intravascular
coagulation (Fig. 4).
Of course, the levels of coagulation proteins are not the only factors that play a role
in hemostatic abnormalities that occur in liver disease. Patients with cirrhosis also
suffer fromdefects of platelet function and number that can contribute to a bleedingtendency.35 However, the platelet defects may also be balanced by the dramatic
increase in the levels of FVIIIa/vWF, which can increase platelet adhesion and allow
localization of hemostatically effective numbers of platelets.36 Hepatic insufficiency
Fig. 4. Hemostatic balance. (A) Under normal conditions there are higher levels of pro- andanticoagulant proteins than are needed for minimal hemostatic function. This functionalexcess allows for a high degree of stabilitythe hemostatic balance tends to be main-tained even under stress. (B) When the levels of the pro- and anticoagulant factors arereduced by hepatic insufficiency, there may not be a tendency to hemorrhage or thrombo-sis/DIC. However, the hemostatic balance is much harder to maintain in the face of stressorssuch as infection.
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can also impair clearance of activated procoagulant and fibrinolytic enzymes, and
increase the impact of any hemostatic perturbation. These phenomena will be
explored further in succeeding sections.
It should be clear from the preceding discussion that the coagulation cascade
model and the common clinical coagulation tests do not reflect the complexity of
hemostasis in vivo. These screening coagulation tests are most sensitive to a defi-
ciency of one or more of the soluble coagulation factors. They are very useful in defin-
ing a deficiency state in patients with a known bleeding tendency. They do not reflect
the roles played by inhibitors, and do not necessarily reflect the risk of clinical bleed-
ing. That does not mean that the PT and aPTT are useless. However, we need to
understand what they can and cannot tell us and interpret them in light of the clinical
setting.
SUMMARY
The coagulation cascade model is essential to interpreting the results of screeningcoagulation tests. However, it does not accurately model how hemostasis occurs in
vivo. More modern models of hemostasis incorporate the active roles of cellular par-
ticipants in directing and controlling the process. Different cell types express different
pro- and anticoagulant properties. They localize different plasma protein components
in a manner that tends to limit the activity of the coagulation reactions to cell surfaces
at a site of injury. In hepatic insufficiency, a reduction in the levels of the pro- and
anticoagulant proteins produced in the liver does not impair thrombin generation until
levels are quite low. However, the ability of the coagulation system to tolerate or
recover from an insult is markedly impaired in liver disease, allowing the system to
be more easily tipped into a state favoring either hemorrhage or thrombosis.
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14. Bauer KA, Mannucci PM, Gringeri A, et al. Factor IXa-factor VIIIa-cell surface
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15. Hung DT, Vu TK, Wheaton VI, et al. Cloned platelet thrombin receptor is neces-
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16. Hoffman M, Monroe DM, Roberts HR. Cellular interactions in hemostasis. Haemo-
stasis 1996;26(Suppl 1):126.
17. Oliver J, Monroe D, Roberts H, et al. Thrombin activates factor XI on activated
platelets in the absence of factor XII. Arterioscler Thromb Vasc Biol 1999;19:
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18. Baglia FA, Walsh PN. Prothrombin is a cofactor for the binding of factor XI to the
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19. Franssen J, Salemink I, Willems GM, et al. Prothrombinase is protected from in-
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20. Lu G, Broze GJJ, Krishnaswamy S. Formation of factors IXa and Xa by the extrin-
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22. Esmon CT, Stenflo J, Suttie JW. A new vitamin K-dependent protein. A phospho-
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scored liver cirrhosis: characteristic changes of plasma levels of protein C versus
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31. Raya-Sanchez JM, Gonzalez-Reimers E, Rodriguez-Martin JM, et al. Coagulation
inhibitors in alcoholic liver cirrhosis. Alcohol 1998;15:1923.
32. Tripodi A, Salerno F, Chantarangkul V, et al. Evidence of normal thrombin gener-
ation in cirrhosis despite abnormal conventional coagulation tests. Hepatology
2005;41:5538.
33. Ben-Ari Z, Osman E, Hutton RA, et al. Disseminated intravascular coagulation in
liver cirrhosis: fact or fiction? Am J Gastroenterol 1999;94:297782.
34. Violi F, Ferro D, Basili S, et al. Association between low-grade disseminated
intravascular coagulation and endotoxemia in patients with liver cirrhosis. Gastro-
enterology 1995;109:5319.
35. Tripodi A, Primignani M, Chantarangkul V, et al. Thrombin generation in patients
with cirrhosis: the role of platelets. Hepatology 2006;44:4405.
36. Lisman T, Bongers TN, Adelmeijer J, et al. Elevated levels of von Willebrand factor
in cirrhosis support platelet adhesion despite reduced functional capacity.
Hepatology 2006;44:5361.
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The Platelet andPlatelet Function
Test ing in Liver Dise as e
Greg G.C. Hugenholtz, BSca, Robert J. Porte,MD, PhDb,
Ton Lisman,PhDa,*
Blood platelets are pivotal cells in the process of hemostasis and thrombosis. Hemo-
stasis is the physiologic process that causes bleeding to cease after injury to the vas-
cular wall injury. Primary hemostasis refers to the formation of a loose platelet plug
on the injured vascular endothelium. Secondary hemostasis refers to the series of
enzymatic reactions eventually leading to the conversion of fibrinogen into fibrin,
which stabilizes the platelet plug.
In chronic and acute liver failure multiple alterations in secondary hemostasis may
be present. These alterations may result from a decreased synthesis of coagulationfactors in the diseased liver, vitamin K deficiency, or a deficiency of vitamin Kdepen-
dent carboxylase.1,2 Whether these alterations lead to an increased bleeding risk has
been questioned in recent publications.35 In patients who have liver disease, a
decrease of the components of the procoagulant system often is accompanied by
a simultaneous decrease of the anticoagulant system. This concomitant decrease in
pro- and anticoagulant factors may explain the weak link between the severity of
bleeding in clinical practice and the level of coagulation abnormalities as assessed
by conventional coagulation tests that fail to test the contribution of the natural inhib-
itors of coagulation to clot formation.610
Recently, Tripodi and co-workers11 used a modified in vitro thrombin-generation
test to investigate thrombin generation in the presence of coagulation inhibitors. These
studies demonstrated that cirrhotic patients maintain the same capacity to generate
thrombin as healthy controls when thrombomodulin, the activator of the anticoagulant
protein C, is added to the test mixture. These results indicate that clot formation in
a Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen,University of Groningen, CMC V, Y2144, Hanzeplein 1, 9713 GZ, Groningen, The Netherlandsb
Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation,University Medical Center Groningen, University of Groningen, BA33, Hanzeplein 1, 9713 GZ,Groningen, The Netherlands* Corresponding author.E-mail address: [email protected](T. Lisman).
KEYWORDS
Primary hemostasis Platelets Platelet function tests Bleeding Liver disease
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patients who have cirrhosis is not necessarily impaired and that secondary hemostasis
in patients who have liver disease in fact often seems to be rebalanced. In vivo how-
ever, thrombin generation is a function not only of pro- and anti-coagulant factors but
also of platelets.12,13 The platelet surface provides a scaffold for the assembly of
coagulation factor complexes, an essential step in the thrombin generation pathway.
Primary and secondary hemostasis therefore are physiologically integrated for
thrombin generation and fibrin formation.
Abnormalities in platelet number and function are common in patients who have
liver disease. Therefore Tripodi and colleagues12 also investigated the effect of these
abnormalities on the generation of thrombin. They found that the capacity of platelets
to support thrombin generation in cirrhotic patients was indistinguishable from that in
healthy subjects when platelet counts were adjusted to similar (normal) levels and
thrombomodulin was added to the experiment. In most cirrhotic patients platelet num-
bers are decreased only moderately. Thus, thrombin generation probably is not af-
fected to a great extent in these patients. In line with the aforementioned studies
assessing secondary hemostasis, these results now challenge the assumption that
in patients who have liver disease alterations in primary hemostasis are inherent to
significant hemorrhagic complications.
Standard diagnostic tests of primary hemostasis such as the bleeding time tradi-
tionally have associated platelet abnormalities with an increased risk of bleeding. In
fact, based on this relationship, many centers justify the use of prophylactic measures,
including platelet transfusion before invasive procedures (such as liver biopsy or tooth
extraction), even though no prospective studies have been conducted to confirm
whether such measures are an effective way to prevent bleeding events in patients
who have liver disease. Moreover, transfusion of platelets in patients who have liverdisease may be associated with serious side effects, such as volume overload, exac-
erbation ofportal hypertension, risk of infection, and risk of transfusion-related acute
lung injury.14 The recent identification of platelet transfusion asanindependent risk
factor for decreased 1-year survival after liver transplantation15 emphasizes the
need for a critical review of the significance of platelet abnormalities and platelet
function tests in patients who liver disease.
PLATELETADHESION AND ACTIVATION UNDER CONDITIONS OF FLOW
After damage to the vascular wall, platelets are recruited from the flowing blood andrapidly adhere to the exposed subendothelial surface. Adhesion to subendothelial
adhesive proteins such as collagen requires the synergistic action of several receptors
(summarized inFig. 1). First, glycoprotein Ib interacts with the plasma protein von Wil-
lebrand factor (VWF), which, when bound to collagen, undergoes a conformational
change revealing several platelet-binding sites. This interaction is transient, merely
slowing down the velocity of platelets, but it enables platelet arrest by the action of
two platelet receptors, integrin aIIb1 and glycoprotein VI (GPVI), which interact directly
with collagen. The interaction of adhered platelets and collagen initiates signal trans-
duction events via glycoprotein VI, resulting in platelet activation. Activated platelets
are able to interact with each other, mediated by the integrinaIIbb3, which can bridgetwo platelets via fibrinogen or VWF.
Platelet activation results in the release of alpha and dense granules, which contain
mediators of secondary platelet activation, such as ADP, or proteins involved in coag-
ulation. At the same time, platelets start synthesizing thromboxane A2 from arachi-
donic acid released from the membrane, also resulting in the secondary activation
of platelets. Stabilization of the platelet plug is mediated further by the formation of
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fibrin through the coagulation system. As the platelet is activated, its surface alters to
provide the appropriate phospholipid scaffold necessary for the assembly of key com-
plexes of the coagulation cascade. Through a series of enzymatic reactions cell-de-
rived tissue factor induces the formation of thrombin, which cleaves fibrinogen into
fibrin monomers. These monomers cross-link into insoluble strands that stabilizethe loose platelet plug.1619
PLATELETS IN LIVER DISEASE
Patients who have liver disease can present with substantial alterations in the pri-
mary hemostatic system. Abnormal platelet numbers and function are common
and traditionally have been thought to contribute to impaired hemostasis in both
acute and chronic liver disease.20 Thrombocytopenia is a general feature of patients
who have advanced disease. It is attributable mainly to increased platelet sequestra-tion in the spleen associated with portal hypertension. Thrombocytopenia also may
be a consequence of decreased thrombopoietin synthesis by the diseased liver.21,22
Alternatively, myelosuppression resulting from acute hepatitis C infection, folic acid
deficiency, or ethanol toxicity may have a negative effect on megakaryocytopoie-
sis.2325 In addition, autoantibodies and low-grade disseminated intravascular coag-
ulation have been related to reduced platelet survival and increased platelet
Fig.1. Platelet plug formation after vascular wall damage under conditions of flow. (A) Slow-ing down of platelets by transient interaction of platelet glycoprotein Ib (GPIb) with vonWillebrands factor (VWF). (B) Stable attachment to the exposed subendothelial surface(eg, collagen) by direct interaction with collagen receptors aIIb1 and glycoprotein VI(GPVI), and indirectly via interaction of platelet integrin aIIbb3 with collagen-bound VWF.(C) Platelet activation by thrombin or by platelet releasates (ADP or thromboxane A2,TXA2). (D) Plateletplatelet interaction mediated by vWF or fibrinogen (Fg) binding toaIIbb3. (FromLisman T, Leebeek FWG. Hemostatic alterations in liver disease: a review onpathophysiology, clinical consequences, and treatment. Dig Surg 2007;24(4):251; withpermission.)
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consumption, respectively.26,27 The presence of disseminated intravascular coagula-
tion in patients who have liver disease is controversial, however.28
Besides the observed changes in platelet numbers, reduced adhesiveness and
impaired aggregation are well described in in vitro experiments involving platelets
from cirrhotic patients.2931 Both intrinsic and extrinsic factors have been proposed
as contributing to the impairment of platelet function.
Platelet dysfunction has been associated with intrinsic factors such as acquired
storage pool defects, decreased thromboxane A2 synthesis, altered transmembrane
signal transduction, and quantitatively decreased glycoprotein Ib and aIIb3 receptors
as a consequence of proteolysis by the overactive fibrinolytic system.3138 On the
other hand, platelet function in vivo may be influenced negatively by several extrinsic
factors. Abnormal high-density lipoproteins, reduced hematocrit, and increased
levels of endothelium-derived nitric oxide and prostacyclin, two potent platelet inhib-
itors, have been suggested as influencing normal platelet function in patients who
have liver disease.3941
The assumption that these alterations inherently lead to an increased bleeding
tendency lacks solid clinical proof, however. In addition, recent data suggest that,
to some degree, elevated levels of VWF compensate for the abnormalities in platelet
number and function.
BLEEDING TIME AND PLATELET AGGREGATION: DIAGNOSTIC TOOLS
FOR BLEEDING RISK?
The bleeding time is the oldest test of platelet function. Basically, it is measuredby inflicting a standardized cut on the volar surface of the forearm using
a blood-pressure cuff on the upper arm. The reproducibility of this test, however,
depends to a large extent on the skills of the technician, the skin thickness, and
ambient temperature, among other factors including possible endothelial dysfunc-
tion.42 In spite of its widespread use as a predictor of bleeding in a variety of dis-
orders, the sensitivity and specificity of the bleeding time remain insufficiently
validated in clinical practice.43
The bleeding time is prolonged in up to 40% of patients who have liver disease.44
Desmopressin, an analogue of vasopressin, shortens the bleeding time in these pa-
tients, probably by enhancing endothelial-derived VWF levels.4547 Randomized trials,however, did not show that desmopressin had any efficacy in controlling variceal
bleeding or in reducing blood loss in patients undergoing partial liver resections or liver
transplantation.4850 This finding indicates that a correction of the bleeding time may
not necessarily result in improvement of primary hemostasis. Moreover, the associa-
tion between a prolonged bleeding time and the degree of liver failure as assessed
by the Child-Pugh score has been shown to be independent of the risk of gastro-
intestinal hemorrhage.51 These findings reflect the outcome of prospective studies
indicating that the bleeding time is an unreliable predictor of bleeding in cirrhotic
patients.52,53
In the past, laboratory testing of platelet function has proved useful for exploringfundamental processes or as a diagnostic tool for hereditary or acquired platelet
defects, but standardization of testing for clinical practice has not yet been
achieved.42,54 In addition, most of the in vitro experiments assessing platelet function
in cirrhotic patients were conducted under static conditions using platelet-rich plasma
and leaving out essential physiologic factors for platelet activation in vivo (eg, red
blood cells and shear stress) that test platelet function in a VWF-dependent manner.
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The platelet function analyser-100 (PFA-100) is a rapid new in vitro test that provides
a quantitative measure of primary hemostasis at high shear stress using citrated whole
blood. This automated device functions with blood flowing under a constant vacuum
through a capillary and a microscopic aperture in a membrane coated with collagen
and agonists. As a result, the closure time of the aperture is a measurement of platelet
adhesion/aggregation.42,55 Experiments with the PFA-100 demonstrated that a pro-
longed closure time can be corrected by elevating the hematocrit in the blood of pa-
tients who have liver disease.30 This finding suggests that the influence of hematocrit
(and other physiologic factors) on platelet function is probably more relevant than the
intrinsic platelet defects commonly found in patients who have liver disease. As yet,
however, no studies have been reported that determine whether the closure time
correlates with clinical outcome.
THE RELEVANCE OF THROMBOCYTOPENIA AND REDUCED PLATELET FUNCTION IN CIRRHOSIS
Thrombocytopenia is mostly mild to moderate in patients who have stable liver dis-
ease, and a mild reduction in platelet counts is in general not associated with severe
bleeding. Moreover, one of the most severe forms of bleeding, variceal hemorrhage, is
mainly a consequence of local vascular abnormalities as well of increased splanchnic
blood pressure, and the contribution of a hemostatic impairment in this situation is de-
batable.56 One therefore can argue that the clinical relevance of thrombocytopenia in
most patients who have liver disease is of questionable significance. In this regard,
liver transplantation is one of the most challenging situations requiring effective hemo-
stasis. With recent advances in surgical experience, technique, and anesthesia care,
however, a considerable number of patients (up to 50% in some centers) undergo theoperation without the need of any blood products.57 In line with this experience, recent
laboratory data show that platelet abnormalities in patients who have cirrhosis are not
apparent when platelet function is tested in models using flowing blood.58,59
As mentioned previously, Tripodi and co-workers12 also showed that platelet func-
tionality, as measured by its capacity to support thrombin generation, is not dimin-
ished in patients who have stable cirrhosis. Recently the authors group also has
revisited platelet function in patients who have liver disease, because previous studies
had already shown that the abnormalities in coagulation and fibrinolysis are not as
severe as thought previously.11,60 These studies have shown that, under physiologic
conditions of flow, platelets from patients who have liver cirrhosis are able to interactnormally with collagen and fibrinogen as long as the platelet count and hematocrit are
adjusted to the levels founds in healthy subjects (Fig. 2A).58 Thus, the previously
described platelet function defects do not seem to be important when tested under
conditions of flow.
In addition, the authors and colleagues recently established that, compared with
healthy subjects, levels of VWF are increased substantially (up to 10-fold) in plasma
from patients who have chronic liver disease.59 This increase in VWF may be the conse-
quence of different mechanisms, such as endothelial cell activation, bacterial infection, or
reduced hepatic clearance.6163Surprisingly, in subsequent experiments, the authors and
colleagues found a greater activation rate and thrombus formation when using plateletsobtained from cirrhotic patients, who have increased levels of VWF, than when using
platelets from healthy controls under normal plasmatic VWF concentrations, provided
platelets in both group were adjusted to similar counts (Fig. 2B).59 These findings suggest
that the increased levels of circulating VWF found in patients who have liver disease may
compensate to a certain extent for any defect in platelet function and for the decrease in
platelet numbers.
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SUMMARY
Patients who have liver disease may present with alterations in the primary hemostatic
system. The standard diagnostic tests, however, are of little use in the identification of
patients who have an increased risk of bleeding. Increasing evidence argues against
Fig. 2. (A) Platelet function testing under flow conditions. Representative micrographs of
platelet deposits on collagen and fibrinogen formed by reconstituted patient blood (plate-let count of 200 000 mL1 and a hematocrit of 40%) and control blood (original magnifica-tion 400). (From Lisman T, Adelmeijer J, de Groot PG, et al. No evidence for an intrinsicplatelet defect in patients with liver cirrhosisstudies under flow conditions. J Thromb Hae-most 2006;4(9):2071; with permission.) (B) Plasma from patients who have cirrhosis supportsplatelet adhesion better than normal plasma. Micrographs of platelet deposits on collagenformed by reconstituted blood with platelets isolated from a patient who has cirrhosisresuspended in plasma from either healthy controls or from patients with cirrhosis (originalmagnification 400). (From Lisman T, Bongers TN, Adelmeijer J, et al. Elevated levels ofvon Willebrand factor in cirrhosis support platelet adhesion despite reduced functionalcapacity. Hepatology 2006;44:58; with permission.)
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the use of the bleeding time as a diagnostic tool for predicting bleeding in patients who
have liver disease. Further research is needed to determine whether newer techniques
can provide a useful substitute for the bleeding time. Thrombocytopenia is moderate
in most patients and generally does not result in significant bleeding events. Also the
role of platelet dysfunction probably is less important than expected. Modern technol-
ogy has improved the study of platelets in vitro because platelet function can be
assessed under more physiologic conditions. Recent in vitro studies demonstrate
that platelet dysfunction in patients who have cirrhosis is not relevant under flow con-
ditions. The capacity of platelets to provide a surface for thrombin generation is not
altered, and high plasma levels of VWF seem to compensate for any decrease in plate-
let function. The precondition for these experimental observations, however, is that
platelet numbers and hematocrit are adjusted to normal levels.
Given the lack of data supporting prophylactic treatment with platelet concentrates
before invasive procedures, and given the experience obtained during liver transplan-
tation, in which platelet count is not routinely corrected before surgery, the routine use
of prophylactic platelet transfusions when performing invasive procedures in patients
who have liver disease is questionable. Exceptions include high-risk procedures in
which bleeding is unlikely to be detected before irreversible damage occurs (eg, place-
ment of an intracranial pressure monitor in a patient in acute liver failure). Prospective
studies are needed to ascertain whether the group of patients who present with both
substantially decreased platelet numbers and a history of severe or refractory bleeding
could benefit from a therapy designed to improve the numbers of platelets (eg, throm-
bopoietin). In addition, the potential role of other confounding variables such as active
infection, renal failure, or changes in lipid composition warrants further investigation.
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H yperfibrinolys isin Liver Diseas e
Domenico Ferro, MDa,b,*, Andrea Celestini, MDb, FrancescoVioli, MDb
The association between liver disease and accelerated fibrinolysis was describedmore than 80 years ago when the rapid reliquidification of incubated, clotted blood
from cirrhotic patients was noted.1 In the current literature the occurrence of hyperfi-
brinolysis in patients who have cirrhosis has been suggested but is still debated.2 The
reasons for this uncertainty probably lie in the lack of appropriate laboratory tests for
the evaluation of hyperfibrinolysis.3 Thus, the assay of individual components rather
than evaluation of the overall fibrinolytic activity has been investigated.35 Nonethe-
less, there is a relative consensus that hyperfibrinolysis may complicate the clinical
course of patients who have cirrhosis or liver failure.69 In a previous study the inci-
dence of hyperfibrinolysis, diagnosed by abnormal euglobulin lysis time, was
36%,10 comparable to most,7,11 but not all, previous reports12 in patients who under-went liver transplantation. Hyperfibrinolysis correlated positively with the severity of
underlying liver disease (the Child-Pugh classification),10,1315 and low-grade systemic
fibrinolysis was found in 30% to 46% of patients who had end-stage liver disease.16
Therefore the debate regarding hyperfibrinolysis in liver disease focused essentially
on the mechanism of hyperfibrinolysis and its role, if any, in the bleeding disorders
complicating the clinical course of liver cirrhosis.
PATHOPHYSIOLOGY OF HYPERFIBRINOLYSIS IN LIVER DISEASE
Imbalance of the Fibrinolytic System
All the proteins involved in fibrinolysis, except for tissue plasminogen activator
(tPA) and plasminogen activator inhibitor 1 (PAI-1), are synthesized in the liver.17
Reduced plasma levels of plasminogen,18 alpha2-antiplasmin,1921 histidine-rich-
glycoprotein,22,23 and factor XIII24 are found in cirrhosis. There is general agreement
that patients who have liver cirrhosis have increased values of tPA13,2527 that
a Department of Experimental Medicine, University of Rome, La Sapienza, Rome, Italyb
Institute of Clinical Medicine I, University of Rome, La Sapienza, Policlinico Umberto I,00181 Rome, Italy* Corresponding author. Institute of Clinical Medicine I, University of Rome, La Sapienza,Policlinico Umberto I, 00181 Rome, Italy.E-mail address: [email protected](D. Ferro).
KEYWORDS
Hyperfibrinolysis tPA Liver disease Variceal bleeding Liver transplantation Aprotinin
Clin Liver Dis 13 (2009) 2131doi:10.1016/j.cld.2008.09.008 liver.theclinics.com1089-3261/08/$ see front matter 2009 Elsevier Inc. All rights reserved.
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probably result from reduced hepatic clearance,28,29 but the measure of plasminogen
activator inhibitor type 1 (PAI-1) gives conflicting results3,25,30,31 and seems to be
influenced greatly by the characteristics of the patients screened. Thus, circulating
levels of PAI-1 are elevated in patients who have chronic liver disease,13,32 but they
are depressed in severe liver failure.13,33 It has been suggested that, in patients who
have severe liver failure, hyperfibrinolysis occurs when plasminogen activation by
tPA is accelerated on the fibrin surface, and decreased levels of PAI-1 and alpha2-
antiplasmin fail to balance it. In contrast, there are high levels of the acute-phase
reactant PAI-1, leading to a shift toward hypofibrinolysis in acute liver failure.8
In the last few years, another plasma protein, thrombin-activatable fibrinolysis inhib-
itor (TAFI), has been identified. It is synthesized by the liver and plays an important reg-
ulatory role in fibrinolysis.3436 Upon activation by thrombin or plasmin, it is converted
to an enzyme (TAFIa) with carboxypeptidase Blike activity that inhibits fibrinolysis
through the removal of C-terminal lysines from partially degraded fibrin.37,38 Particular
attention has been focused on TAFI on the assumption that its decreased levels might
account for hyperfibrinolysis in cirrhosis.39 Lisman and colleagues40 tested this hy-
pothesis by measuring the individual components of fibrinolysis and by using a global
test to assess the overall plasmatic fibrinolytic capacity. They concluded that the de-
ficiency of TAFI in cirrhotic patients is not associated with increased plasma fibrinoly-
sis resulting from the concomitant reduction of profibrinolytic factors. Colucci and
colleagues,41 however, showed TAFI antigen and activity levels are reduced markedly
in cirrhotic patients and concluded that in vitro plasma hyperfibrinolysis is caused
largely by defective TAFIa generation resulting from low TAFI levels. These different
results probably can be explained by the different designs of the global fibrinolysis
assays performed in the two studies. A recent report described a new method for as-sessing the global fibrinolytic capacity of both the extrinsic and the intrinsic pathway
and confirmed the presence of hyperfibrinolysis in chronic liver disease.42
At the origin of hyperfibrinolytic state in liver cirrhosis, physiologic stress, including
infection, may be involved through the increased release of tPA.43 Extravascular acti-
vation of the fibrinolytic system also has been suggested as playing a role. Ascites has
fibrinolytic activity,44 and its absorption could affect systemic fibrinolysis. Thus, be-
cause ascites fluid re-enters the systemic circulation via the thoracic duct (a natural
peritoneovenous shunt with up to 20 L reabsorbed daily), this phenomenon could
be a trigger for accelerated fibrinolysis.
Accelerated Intravascular Coagulation and Fibrinolysis
The significance of low-grade disseminated intravascular coagulation in liver cirrhosis
is another debated issue.33,4549As with hyperfibrinolysis, the variable characteristics
of the patients screened may explain the divergent results. Thus, with the use of highly
sensitive tests such as prothrombin fragment 112 (a marker of in vivo thrombin gen-
eration), D-dimer (a product of thrombin and plasmin activation), high-molecular-
weight fibrin/fibrinogen complexes, or soluble fibrin, a particular profile, accelerated
intravascular coagulation and fibrinolysis (AICF), was detected in about 30% of cir-
rhotics, depending on the degree of liver failure.2,49,50 AICF seems to occur predom-inantly in patients who have moderate-to-severe liver failure but is not detected in
compensated patients51 AICF probably results from the formation of a fibrin clot
that is more susceptible to plasmin degradation because of elevated levels of
tPA or the presence of dysfibrinogen. A reduced release of PAI to control tPA
and lack of alpha2-antiplasmin to quench plasmin activity promotes secondary
hyperfibrinolysis.
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An additional stress, such as infection, may influence these processes with a conse-
quent imbalance of the clotting and fibrinolytic system.3 In patients who have acute or
chronic liver disease, an impairment of the reticuloendothelial system and/or the
presence of portosystemic shunts may lead, in the absence of sepsis, to enhanced
endotoxemia into the systemic circulation.52 In decompensated liver cirrhosis, high
levels of circulating endotoxin were correlated with monocyte expression of tissue
factor mRNA, prothrombin factor 112, and D-dimer, suggesting a direct relationship
between clotting activation and endotoxemia.53,54 This hypothesis was supported by
the decrease of clotting and fibrinolytic activation after the reduction of endotoxemia
obtained with nonabsorbable antibiotics.54
HYPERFIBRINOLYSIS AND BLEEDING
Bleeding is a frequent and often severe complication of liver cirrhosis.55 Variceal
hemorrhage occurs at a yearly rate of 5% to 15%. The most important predictor ofhemorrhage is the size of varices. Patients who have large varices are at the highest
risk of first hemorrhage (15% per year).56 Other predictors of hemorrhage are decom-
pensated cirrhosis and the endoscopic presence of red wale marks.56 Bleeding from
esophageal varices is associated with a mortality of at least 20% at 6 weeks,5759 and
late rebleeding occurs in approximately 60% of untreated patients, generally within 1
or 2 years of the index hemorrhage.60,61 Hemodynamic alterations secondary to portal
hypertension are considered the main cause of gastrointestinal bleeding in cir-
rhotics.62,63 The role played by the coagulopathy of cirrhosis in gastrointestinal bleed-
ing is still unclear.64,65 Coagulopathy does not seem to play a major role in initiating
bleeding, but a relationship between severity of bleeding and coagulation defectshas been postulated.13 Variceal bleeding is more severe, more difficult to control,
and more likely to recur in patients who have advanced liver failure, which presents
as defects of primary and secondary hemostasis.66,67 Otherwise, the recent literature
indicates the hemostatic changes either impair or promote hemostasis, thus suggest-
ing a rebalanced hemostatic system in liver disease.17
Previous studies suggested that hyperfibrinolysis may be a good predictor of gas-
trointestinal bleeding.68,69 Consistent with these preliminary reports, the authors
demonstrated that fibrinogen degradation products in the serum increase the risk of
bleeding in cirrhosis;70 however, the methodologic problems related to this assay
rendered these data difficult to interpret.46 In another report, hyperfibrinolysis, as as-sessed by high values of D-dimer and tPA activity, was found to be a predictor of the
first episodeof upper gastrointestinal bleeding in cirrhotic patients who had portal hy-
pertension.71 Hyperfibrinolysis was associated closely with the degree of liver failure
and ascites and constituted a further risk, in addition to variceal size, in predicting gas-
trointestinal bleeding.71 The interference of hyperfibrinolysis with clotting activation
and platelet function might account for this association. Thus, as a consequence of
hyperfibrinolysis, clotting activation may be delayed because of the consumption of
clotting factor and inhibition of fibrin polymerization.72 Hyperfibrinolysis also reduces
platelet adhesion and aggregation by degradation of von Willebrands factor and
fibrinogen platelet receptors (glycoprotein Ib and IIb/IIIa).73,74 Finally, hyperfibrinolysismay provoke clot lysis by inducing platelet disaggregation and disruption of the hemo-
static plug.75
These arguments suggest that when esophageal varices rupture, hyperfibrinolysis
may delay primary hemostasis or clotting activation or induce disruption of the hemo-
static plug, thereby aggravating variceal bleeding and increasing the likelihood of
recurrence.73,76
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HYPERFIBRINOLYSIS IN LIVER TRANSPLANTATION
In earlier studies, up to 75% of liver transplantations required a blood transfusion, and
the mortality andmorbidity at 1 year were related closely to the quantity of blood com-
ponents required.77 Although refinements in surgical techniques have reduced the
need for blood transfusions, this population remains at a significant risk of bleedingproblems. Since the 1960s, alterations in hemostatic system and activation of fibrino-
lysis pathway have been considered to be responsible for a hemorrhagic diathesis.78
The risk of bleeding in the preanhepatic stage is related directly to the preoperative
hemorrhagic risk related to the underlying liver disease. During this phase, in fact,
there usually are no changes in the hemostatic profile, and there are no significant dif-
ferences between liver transplantation and other abdominal interventions in cirrhotic
patients.
During the second anhepatic stage, a veno-venous bypass maintains venous return,
and most vessels are clamped off; so there is no hepatic function and no risk of
surgical bleeding. Life-threatening blood loss may occur, however. Many studieshave reported enhanced fibrinolytic activity during this period,79 and the lack of tPA
clearance and the reduction of a2-antiplasmin may be responsible for enhanced
primary fibrinolysis.49
Reperfusion of the liver during the postanhepatic phase is the crucial point of the
intervention; although the surgical trauma is comparable to the previous stages, the
amount of blood loss is completely different. Some patients may present with uncon-
trollable diffuse bleeding within a few minutes after reperfusion. Primary fibrinolysis
seems to play a pivotal role in this phase also.49,78 Porte and colleagues12 demon-
strated that the rise of tPA during the anhepatic phase is followed by a dramatic
increase after reperfusion in almost three quarters of patients who undergo liver trans-plantation. Usually hyperfibrinolysis subsides within an hour, but in damaged donor
liver a sustained increased fibrinolytic activity may be observed.80 The endothelium
of the donor liver is an important source of tPA; the ischemic damage to the graft
during preservation may explain the dramatic increase in plasminogen activators. In
the postoperative period, a reduction in platelet count is related to blood loss. Both
thrombopoietin plasma levels and an increase in platelet consumption contribute to
the development of thrombocytopenia. The platelet count usually normalizes after
2 weeks.81
The monitoring of coagulation and fibrinolysis activity is an essential element of care
during liver transplantation. Among the diagnostic tests usually performed (listed in
Table 1), thromboelastography highlights alterations at every step in the cascade
from clot formation to its lysis (see also the article by A. Tripodi in this issue). Thus
with thromboelastography it is possible to know if bleeding results from a failure to
provide adequate surgical hemostasis, whether there are platelet dysfunction or
anomalies in coagulation proteases or their inhibitors, and whether the blood loss
is associated with early, excessive fibrinolysis. Finally, thromboelastography allows
a rational approach to the correct used of blood components in transfusion or drug
therapy.82
THERAPY
Antihyperfibrinolytic therapy is an important component of hemostatic therapy
in hepatic diseases (see also the article by Shah and Berg in this issue). Both
eaminocaproic acid (EACA) and tranexamic acid interfere with the plasminogen bind-
ing to the fibrin, reducing the conversion of plasminogen to plasmin; although EACA
and tranexamic acid have been used widely to prevent blood loss during liver
Ferro et al24
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Table1
Diagnostic tests in hyperfibrinolysis
Laboratory Test Methodology Normal Range
Clot lysis time In vitro clot dissolution 3060 minutes
Euglobin lysis time In vitro clot dissolution withoutplasmin inhibitors
527 hours
D-dimer assay Determination by lateximmunoagglutination assay
0.00.4 mg fibrinogen equiva
Fibrinogen degradation productsassay Determination by lateximmunoagglutination assay < 5mg/mL
tPA assay Binding to the wells of a microtiterplate by anti-tPA monoclonalantibodies
0.22.0 IU/mL
Thromboelastogram clot lysis index Thromboelastography Amplitude at 60 minutes asa percentage of the maximamplitude (< 40%)
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transplantation, the evidence base for their efficacy is limited. Only a single random-
ized trial, performed 20 years ago,11 demonstrated the efficacy of EACA in reducing
blood cell transfusion; moreover studies testing the usefulness of tranexamic acid
have reported divergent results; trials that used high dosage (40 mg/kg/hour), reported
a significant reduction ofbleeding,83 but no efficacy was found when this drug was
used at lower dosages.84 Thromboembolic complications may occur with a high-
dose regimen, and the optimal dose of tranexamic acid for orthotopic liver transplan-
tation is still unknown.
Aprotinin is a serin-protease inhibitor that reduces fibrinolytic activity by inhibiting
plasmin and kallicrein.85 This drug has been used in liver transplantation since 1990.
Because randomized trials have shown a reduction in the need for blood transfusion
of about 30%,86 aprotinin now is the most widely used antifibrinolytic drug during liver
transplantation. It is usually administered as 2 106 units over 30 minutes followed by
continuous infusion of 0.5 106 units/hour. Aprotinin and other antifibrinolytic agents
are potentially associated with two important complications: the development of
thromboembolic events and the induction of acute renal tubular necrosis. A recent
meta-analysis that included almost 1500 patients, however, demonstrated that the
administration of antifibrinolytic therapy during liver transplantation is not significantly
associated with an increased risk of thromboembolism.87 Similarly, a recent random-
ized trial that enrolled about 1000 patients demonstrated that aprotinin is associated
with a major risk of developing transient renal dysfunction during the first days after
orthotopic liver transplantation, but it is not associated with a long-term renal disease
or increased mortality.88
SUMMARY
Although it has been difficult to assess its overall magnitude, and debate remains,
there is a relative consensus that hyperfibrinolysis can complicate the overall clinical
course of liver cirrhosis, especially in cases of moderate-to-severe liver failure. Primary
imbalance of the fibrinolytic system seems to be related to higher circulating levels of
tPA, but accelerated intravascular coagulation with secondary hyperfibrinolysis also
has been reported overall in patients who have liver failure. Hyperfibrinolysis may
delay primary hemostasis, thereby aggravating variceal bleeding and making recur-
rence more likely. Liver transplantation may be associated with a dramatic increasein fibrinolytic activity, especially during the reperfusion phase; thus, some patients
may present with uncontrollable bleeding, requiring blood transfusion and specific
antifibrinolytic therapy. At present, aprotinin, a plasmin inhibitor, is the most widely
used antifibrinolytic drug, because it reduces the need for blood transfusion by about
30%; moreover, although the use antifibrinolytic drugs may be related to thromboem-
bolic events and the occurrence of renal tubular necrosis, recent evidence has
demonstrated that the use of aprotinin is not associated with these adverse events.
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